Production of tablet by means of press-mould with application of powder mixture with hydrogen-containing material

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to a method of manufacturing a tablet by pressing a powder mixture in a press-mould plate with the formation of a tablet form, with the powder mixture including a pharmaceutically active substance and hydrated sugars, as well as exposure of the tablet form to radiation for a period of time, sufficient for heating the hydrogen-containing material in the tablet form to a temperature higher than its dehydration temperature with the tablet formation.

EFFECT: increase of production efficiency.

21 cl, 14 dwg, 3 ex, 3 tbl

 

Cross-references to related inventions

The present application claims the priority of provisional application U.S. No. 61/245315, filed September 24, 2009, provisional application U.S. No. 61/255582, filed October 28, 2009, provisional application U.S. No. 61/314629, filed March 17, 2010, and provisional application U.S. No. 61/358167, filed on 24 June 2010. The full contents of the above patent applications in the U.S. for any purpose included in the text of the present document by reference.

Background of the invention

Pharmaceutical preparations intended for oral administration, as a rule, are in the form of tablets. The tablet is swallowed whole, chewed, or sucking in the mouth. Soft pills are chewed or sucking in the mouth, often used in cases where the appointment of a pill to swallow entirely inappropriate. In the case of chewable tablets chewing contributes to the disintegration of the components of the tablet particles and can increase the rate of absorption in the digestive tract. Soft tablets also have the advantage in those cases where it is desirable to provide access to a pharmaceutically active substance at the local introduction into the oral cavity or throat to ensure local impact and (or) systemic absorption. Soft tablets are also used to obleceni� administration of medicines to children and elderly patients. Soft lozenges in the mouth before swallowing particularly preferred when administered to children as a dosage form that meets their requirements.

In General, soft pills are manufactured by pressing a mixture of powdered ingredients, and they generally contain a pharmaceutically active substance, flavor and (or) binders. The powder mixture, usually served in a mold cavity of a tablet press and tablet form by application of pressure. The hardness of the tablets manufactured directly depends on when the pressing pressure and the compatibility of the ingredients in the composition. Softer pill easy to read, can be manufactured by applying a lower pressure. Manufactured tablet is softer, but also more fragile and brittle, and that severely, its production involves a complex and expensive process steps. Examples of soft tablets for dissolution in the mouth without chewing described in U.S. patents №№ 5464632, 5223264, 5178878, 6589554 and 6224905.

There is a need in pleasant from an aesthetic point of view, chewable tablets and tablets for dissolution in the oral cavity, manufactured using a tabletting machines with the press, usually used for the production of dense and solid tablet�to to swallow. When using low compression forces such machines typically form a very fragile tablets with insufficient strength during packaging, transportation and storage. The present invention relates to the disclosure of the technological process of manufacture of tablets, for example, chewable tablets or tablets for dissolution in the oral cavity, by heating (e.g., radio frequency heating) water-containing material, in which the possible use of high-speed tabletting machines.

Brief description of the invention

In one aspect, the present invention relates to a method of making a tablet by compacting a powder mixture in the plate of the mold with the formation of the preformed shape, wherein the powder blend includes a pharmaceutically active substance and a water-containing material, and impact on the tableted form of radiation for a sufficient time to heat the water-containing material in form of tablets to a temperature above its temperature of dehydration with the formation of pills. In one embodiment of the radiation is a radio frequency ("RF") radiation.

Other distinctive features and advantages of the present invention will be clear from the text of the detailed description of the invention and its formula.

Brief opisaniemopyta

FIG. 1A-F represent images in a cross-section side view of a variant embodiment of the invention, showing the manufacturing process of tablets from 4a powder mixture 4 in the plate of the mold 2.

FIG. 2A-H presents images in a cross-section side view of a variant embodiment of the invention, showing the manufacturing process of two-layer tablets 12 from powder mixtures 10 and 11 in the plate of the mold 2.

FIG. 3A-G are the images in a cross-section side view of a variant embodiment of the invention, showing the manufacturing process of tablet 40 containing preformed inserts 30 and 31, of the powder mixture 20 in the plate of the mold 2.

FIG. 4A and 4B shows a view in perspective of the machine with rotary indexing table 195.

FIG. 5A and 5B presents a top view of the machine with rotary indexing table 195 in stop position.

FIG. 6A and 6B shows a view in section of the lower moulding of the node 110 in a position corresponding to the beginning of the production cycle.

FIG. 7 presents a sectional view of the machine with rotary indexing table and an RF unit 195 to pressing a powder mixture 101.

FIG. 8 shows a sectional view of the machine with rotary indexing table and an RF unit 195, which shows the manufacturing process of tablets 101a.

FIG. 9 shows a sectional view of localityname tablets 160 to eject the tablets 101a.

FIG. 10 shows a sectional view of the block popping pills 160 after popping pills 101a in blister 190.

FIG. 11A-D rendered image in cross section alternative embodiments of the molding devices and plates of the mold.

FIG. 12 A-D rendered image in cross section alternative embodiments of the molding devices and plates of the mold.

FIG. 13A shows a view in cross section of the molding devices having an undulating surface.

FIG. 13B shows a view in perspective of the molding devices having an undulating surface.

FIG. 14 shows a view in cross section of the molding devices having protuberances on the surface.

Detailed description of the invention

It is assumed that the specialist, based on this description, can utilize the present invention to the maximum extent. The following specific embodiments of the invention can be considered only as examples, which in no way limit the essence of the present patent application.

If not otherwise indicated, as used herein, technical and scientific terms have the same meanings as in the field of knowledge that applies the present invention. In addition, all publication of the application for a patent, patents and other references in this document sources included therein by reference. Everything used in this document percentages, unless otherwise noted, are specified by weight.

As indicated above, in one aspect, the present invention relates to a method of making a tablet by compacting a powder mixture in the plate of the mold with the formation of the preformed shape, wherein the powder blend includes a pharmaceutically active substance and a water-containing material, and impact on the tableted form of radiation for a sufficient time to heat the water-containing material in form of tablets to a temperature above its temperature of dehydration with the formation of the tablets.

Powder mix

As indicated above, the tablet is manufactured by compacting a powder mixture containing a pharmaceutically active substance (discussed herein), a water-containing material (discussed herein) and optionally pharmaceutically acceptable carrier. The media contains one or more appropriate excipients to form tablets. Examples of appropriate excipients include but are not limited to, fillers, adsorbents, disintegrants, lubricants, sliding substances, sweeteners, su�errestrial, flavouring agents, antioxidants, preservatives, thickeners, and mixtures thereof. In the same powder particle mixture may be present one or more of the above ingredients.

Acceptable excipients include, among others, carbohydrates (as defined herein) and water insoluble plastically deformable materials (e.g., microcrystalline cellulose or other cellulose derivatives), and mixtures thereof.

Acceptable adsorbents include, among others, water-insoluble adsorbents such as dicalcium phosphate, tricalcium phosphate, selectiona microcrystalline cellulose (e.g. available on the market under the brand name PROSOLV production PenWest Pharmaceuticals, Patterson, new York), magnesium alumosilicate (for example, marketed under the trademark NEUSILIN (Fuji Chemical Industries (USA) Inc., G. Robbinsville, state of new Jersey)), clay, silica, bentonite, zeolites, magnesium silicate, hydrotalcite, veegum, and mixtures thereof.

Examples of acceptable disintegrants include, among others, the sodium salt of glycolate starch, crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, starches, microcrystalline cellulose and mixtures thereof.

Examples of acceptable lubricants include, among other things, long-chain fatty acids and their salts,such as magnesium stearate and stearic acid, talc, glycerine waxy substance, and mixtures thereof.

Examples of valid moving substances include, inter alia, colloidal silicon dioxide.

Examples of sweeteners include, among others, synthetic or natural sugars; artificial sweeteners such as saccharin, saccharin sodium, aspartame, Acesulfame, thaumatin, glycyrrhizin, Sucralose, dihydrochalcone, alitum, miraculin, monellin and stevioside; sugar alcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol and xylitol; sugars extracted from sugar cane and sugar beet (sucrose), dextrose (also called glucose), fructose (also called levulose) and lactose (also called milk sugar); isomalt, and their salts and mixtures.

Examples of superathletes include, among others, croscarmellose sodium, the sodium salt of glycolate starch and cross-linked povidone (polyplasdone). In one embodiment, the implementation of the tablet contains up to about 5% by weight. such superathlete.

Examples of flavors include, among other things, essential oils, including distilled, solvent extracted or cold pressed, crushed flowers, leaves, peeled or turned into the fibrous mass of the whole fruit that contains a mixture of alcohols, esters, aldehydes and lactone�; essences including either diluted solutions of essential oils or mixtures of synthetic chemicals blended to simulate the natural smells of fruit (e.g., strawberry, raspberry and blackcurrant); artificial and natural smells of beer and spirits, such as brandy, whisky, rum, gin, sherry, port and wine, tobacco, coffee, tea, cocoa and mint; fruit juices including juice, squeezed from the washed and peeled fruits, such as lemon, orange and lime, sprouts, mint, peppermint, Wintergreen, cinnamon, cocoa, vanilla, liquorice, menthol, eucalyptus, anise seed, nuts, e.g., peanuts, coconut, hazelnut, chestnut, walnut and Cola nut, almonds, raisins; sugar, flour or parts of plant materials, including plant parts of tobacco, such as the genus Nicotiana, in amounts slightly increase the level of nicotine, and ginger.

Examples of the antioxidants include Tocopherols, ascorbic acid, sodium pyrosulfite, stabilizer, butylated hydroxyanisole, ethylenediaminetetraacetic acid and its salts, and mixtures thereof.

Examples of preservatives include, among others, citric acid, tartaric acid, lactic acid, xiantao acid, acetic acid, benzoic acid and sorbic acid, and mixtures thereof.

Examples of thickeners include, addition to its natural� other things, pectin, polyethylene oxide and carrageenan, and mixtures thereof. In one of the embodiments of the invention the thickening agent is used in an amount from about 0.1% to about 10% by weight.

In one embodiment, the powder mixture has an average particle size less than 500 microns, such as from about 50 microns to about 500 microns, such as from about 50 microns to 300 microns. In particular, particles of this size are used in direct compression.

In one embodiment, the tablet may be manufactured from a powder mixture, essentially not containing hydrated polymers. In this document, the term "essentially does not contain" means a content of less than 5%, e.g. less than 1%, e.g., less than 0.1%, for example, the complete absence (0%). Such composition is preferred to maintain the profile of dissolution from immediate-release, making possible to reduce processing costs and material and provide an optimal physical and chemical stability of the tablet.

In one embodiment of the powder blend/tablet essentially does not contain water-insoluble excipients for direct compression. Water-insoluble fillers include microcrystalline cellulose, microcrystallinecellulose for direct compression, cellulose, water-insoluble cellulose, starch, corn starch, and modified starches. As described in the present embodiment, the phrase "essentially does not contain" means a content of less than 2%, e.g. less than 1% or no.

Water-containing material

The powder mixture or tablet, constituting the subject of the present invention, includes at least one water-containing material. Examples of water-containing materials include, in particular, the materials in which water is chemically related materials (e.g. hydrated salts or hydrated sugar), materials in which water is adsorbed or absorbed (e.g., a porous material, such as silicon oxide and micro sponges), as well as materials containing encapsulated water (e.g., capsule, liquid filled).

In one embodiment of the powder blend/tablet contains at least one hydrated salt. Examples of hydrated salts include, among others, the hydrate of sodium sulfate, a hydrate of sodium carbonate, hydrate of calcium chloride, hydrate sodium hydrophosphate, and mixtures thereof. In one embodiment of the hydrated salt has a molecular weight ranging from about 150 to about 400 daltons, for example, from approx�proximately 200 to about 350 daltons.

In one embodiment of the powder blend/tablet contains at least one hydrated sugar. Examples of hydrated sugars include, among other things, dextrose monohydrate.

In one embodiment of the powder blend/tablet contains at least one material, in which water is adsorbed or absorbed. Examples of such materials include, including, pyrogenic silica; colloidal silica, e.g., colloidal dioxide Cremia; silicates, e.g., calcium silicate, aluminum silicate, metasilicate of magnesium-aluminum (for example, the material NEUSILIN, US-2 production Fuji Chemical Ltd) and magnesium silicate; clays; zeolites; and veegum.

In one embodiment of the powder blend/tablet contains at least one liquid-filled capsule. In yet another embodiment of the water released from the capsules when the gap, and the gap is caused by the use of radiation.

Hydrous(s) material(s) may be from approximately 0.01 to approximately 70 percent of the powder mixture/tablets, for example, from about 1 to about 50 percent, e.g. from about 1 to about 30 percent, e.g. from about 2 to about 10 percent of the powder mixture/tablet.

Carbohydrates

In about�nom embodiment of the powder blend/tablet contains at least one carbohydrate. The carbohydrate may (i) upon contact with the water released from the water-containing material, to participate in the connection of the powder mixture in a tablet, (ii) to increase the solubility and improve the taste of the pills, (iii) facilitate the distribution of water-containing material over a wider surface area, and (iv) dilute pharmaceutically active substance and mitigate its effect. Examples of carbohydrates include, among other things, burn the water-soluble carbohydrates, such as sugars (e.g., dextrose, sucrose, maltose, isomalt and lactose), starches (e.g., corn starch), sugar alcohols (e.g. mannitol, sorbitol, maltitol, aritra, lactitol and xylitol) and starch hydrolysates (e.g., dextrins and maltodextrins).

The carbohydrate(s) may be from approximately 5 to approximately 95 percent of the powder mixture/tablets, for example, from about 20 to about 90 percent, or from about 40 to about 80 percent of the powder mixture/tablets. In one embodiment of the powder blend/tablet essentially does not contain (for example, does not contain) water-reactive binders or fusible binder and carbohydrate fuses dosage form upon irradiation (e.g., RF irradiation). In this embodiment, the implementation of the term "essentially does not contain�it" denotes a content of less than 0.1 percent, for example, 0%.

Binder material, water-reactive

In one embodiment of the powder blend/tablet constituting the subject of the present invention, contains at least one binder material, water-reactive. Under binding material, water-reactive, refers to the material or reacting hydrated upon contact with water (e.g., released from the hydrous material during irradiation) and contributing to the connection of the powder mixture in a tablet. Examples of such materials include, including, hydradermie polymers and hydrocolloids. Valid gidratirutmi polymers include, including starch, modified starch, methyl cellulose and hydroxypropyl cellulose. Valid hydrocolloids include, including, gelatin, Galanova gum, carrageenan and pectin.

Fusible binder

In one embodiment of the powder blend/tablet constituting the subject of the present invention, includes at least one fusible binder. In one embodiment of the fusible binder has a melting point from about 40°C to about 140°C, for example, from about 55°C to about 100°C. the Softening or melting of the fusible binder (substances) leads to sintering t�platerowanie form by linking the softened or molten binder with a pharmaceutically active substance and (or) other ingredients in molded powder mixture.

In one embodiment of the fusible binder is a binder that melts the RF radiation. Under a binder that melts the RF radiation, refers to the solid binder, is able to soften or to melt under the effect of RF radiation. Binder, melting of RF radiation, as a rule, is polar and may solidify or harden when cooled.

In one embodiment of the fusible binder is a binder, not fusible RF radiation. In this embodiment of the powder mixture contains an auxiliary substance, which is heated under the effect of RF radiation (e.g., polar excipient), and the resulting heat can soften or melt the fusible binder. Examples of such excipients include polar liquids such as water and glycerin; powdered metals and metal salts, e.g., iron powder, sodium chloride, aluminum hydroxide and magnesium hydroxide; stearic acid; and sodium stearate.

Examples of valid meltable binders include fats, for example coconut oil, hydrogenated vegetable oil, such as stone fruits,palm oil, cottonseed oil, sunflower oil and soybean oil; mono-, di - and triglycerides; phospholipids; cetyl alcohol; waxes such as Carnauba wax, spermaceti wax, beeswax, candlelike wax, shellac wax, microcrystalline wax and paraffin wax; water-soluble polymers, such as polyethylene glycol, polycaprolactone, GlycoWax-932, glycerides, lauroyl-macrogoal-32 glycerides of stearoyl-macrogoal-32; oxides and esters of sucrose.

In one embodiment of the fusible binder is a fusible RF radiation binder and fusible RF radiation binder is a polyethylene glycol (PEG), e.g., PEG-4000. Especially preferred fusible RF radiation binder is PEG containing at least 95% by weight. of PEG particles smaller than 100 microns (measured by traditional means, e.g., by light scattering or laser radiation, or by particle size analysis), with a molecular weight of from 3000 to 8000 daltons.

In one embodiment of the fusible binder is hydrated. In yet another embodiment of the irradiation-fusible binder releases the powder mixture water. In one embodiment, the implementation of hydrated fusible binder contains up to 60 percent, for example�EP, to approximately 50 percent water by weight.

Binder(s) substance(s) may be from approximately 0.01 to approximately 70 weight percent. blend powder/pills, for example, from about 1 to about 50 percent, e.g. from about 10 to about 30 percent of the powder mixture/tablet.

Pharmaceutically active substance

The powder mixture or tablet, constituting the subject of the present invention, includes at least one pharmaceutically active substance. The term "pharmaceutically active substance" means a substance (for example, the connection is allowed or approved by FDA food and drug administration, European medicines Agency or any successor as a vehicle for oral use in the treatment of a pathological condition or disease. Acceptable pharmaceutically active agents include analgesics, anti-inflammatory, antipyretics and antihistamines, antibiotics (e.g., antibacterial, antiviral and antifungal agents), antidepressants, antidiabetic, antispasmodic, aphrodisiac, appetite suppressants, bronchodilators, cardiovascular drugs�record means (for example, statins), for the treatment of Central nervous system, cough remedies, decongestants, diuretics, expectorants, drugs for treatment of diseases of the gastrointestinal tract, anesthetics, mucolytics, muscle relaxants, agents for the treatment of osteoporosis, a stimulant, nikotinsoderzhaschie funds and sedatives.

Examples of agents used to treat gastrointestinal tract, include, antacids such as aluminum-containing pharmaceutically active agents (e.g., aluminum carbonate, aluminum hydroxide, carbonate dihydroxyaluminum sodium aluminum phosphate), bicarbonates pharmaceutically active substances, bi containing pharmaceutically active agents (e.g., bismuth aluminate, bismuth carbonate, subcarbonate bismuth, subgallate bismuth and subnitrate bismuth), calcium-containing pharmaceutically active agents (e.g., calcium carbonate), glycine, magnesium-containing pharmaceutically active agents (e.g., magaldrate, magnesium aluminosilicates, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide and magnesium trisilicate), phosphate-containing pharmaceutically active agents (e.g., aluminum phosphate or calcium phosphate), potassium-containing pharmaceutically active agents (e.g., bicarb�NAT potassium), sodium pharmaceutically active substances (eg, sodium bicarbonate), and silicates, laxative drugs, such as softening stool laxatives (e.g., docusate) and stimulant laxatives (e.g., Bisacodyl); antagonists H2-receptor antagonists such as famotidine, ranitidine, cimetidine and nizatidine; proton pump inhibitors such as omeprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole and lansoprazole; gastrointestinal cytoprotectors such as sucralfate and misoprostol; gastrointestinal prokinetics, such as prucalopride; antibiotics active against H. pylori, such as clarithromycin, amoxicillin, tetracycline and metronidazole; antidiarrheal agents such as bismuth subsalicylate, kaolin, Diphenoxylate and loperamide; glycopyrrolate, pain relievers such as mesalamine; antiemetics, such as ondansetron, this drug, diphenhydramine, dimenhydrinate, meclizine, promethazine, and hydroxizin; probiotic bacteria including, but not limited to, lactic acid bacteria, lactase, racecadotril; carminative drugs, such as polydimethylsiloxane (e.g., Dimethicone and simethicone, including those described in U.S. patents №№ 4906478, 5275822 and 6103260); their isomers and pharmaceutically acceptable salts and Pro-drug forms (e.g., esters).

PR�measures anesthetic, anti-inflammatory and antipyretic agents include non-steroidal anti-inflammatory drugs (NSAIDs) such as propionic acid derivatives (e.g., ibuprofen, naproxen, Ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, Florien, pirprofen, carprofen, oxaprozin, pranoprofen and suprofen) and cyclo-oxygenase inhibitors such as celecoxib, acetaminophen, acetylsalicylic acid, derivatives of acetic acids such as indomethacin, diclofenac, sulindac, and tolmetin, the derivative Funambol acids, such as mefenamic acid, meclofenamate acid and flufenamic acid, the derivatives biphenylcarboxylic acid, such as diflunisal and flufenisal; oxicam, such as piroxicam, sudoxicam, isoxicam and meloxicam, their isomers and pharmaceutically acceptable salts and Pro-drug forms.

Examples of antihistamines and decongestants include, among others, bromopheniramine, chlorcyclizine, dexbrompheniramine, bromhexin, phenindamine, Pheniramine, pyrilamine, thonzylamine, tripolidine, ephedrine, phenylephrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, terfenadine, Fexofenadine, naphazoline, Oxymetazoline, montelukast, propylhexedrine, triprolidine, clemastine, acrivastine, promethazine, ox�mamasan, mequitazine, buclizine, Bromhexine ketotifen, ebastine, oxatomide, Xylometazoline, loratidine, desloratadine and cetirizine, their isomers, pharmaceutically acceptable salts and esters.

Examples of cough and expectorants include, among others, diphenhydramine, dextromethorphan, noscapine, chlophedianol, menthol, benzonatate, Ethylmorphine, codeine, acetylcysteine, carbocisteine, Ambroxol, belladonna alkaloids ordinary, Sabrina, guaiacol and guaifenesin, their isomers, pharmaceutically acceptable salts and Pro-drug forms.

Examples of muscle relaxants include cyclobenzaprine, chlorzoxazone, metaxalone, orphenadrine and Methocarbamol, their isomers, pharmaceutically acceptable salts and Pro-drug forms.

Examples of stimulants include caffeine.

Examples of sedatives include, among others, sleep AIDS such as antihistamines (e.g., diphenhydramine), eszopiclone and zolpidem, and their pharmaceutically acceptable salts and Pro-drug forms.

Examples of suppressing appetite include, but not limited to, phenylpropanolamine, phentermine and diethylcathinone, their pharmaceutically acceptable salts and Pro-drug forms.

Examples of anesthetics (e.g., in the treatment of sore throat) include, among others, dyclonine, benzocain� and pectin, their pharmaceutically acceptable salts and Pro-drug forms.

Examples of statins include, among others, atorvastin, rosuvastatin, fluvastatin, lovastatin, simvastatin, atorvastatin, pravastatin, their pharmaceutically acceptable salts and Pro-drug forms.

In one embodiment, the implementation of the pharmaceutically active substance added to a tablet is selected from phenylephrine, dextromethorphan, pseudoephedrine, acetaminophen, cetirizine, aspirin, nicotine, ranitidine, ibuprofen, Ketoprofen, loperamide, famotidine, calcium carbonate, simethicone, chlorpheniramine, methocarbomal, chlormadinone, ascorbic acid, pectin, dyclonine, benzocaine, menthol, their pharmaceutically acceptable salts and Pro-drug forms.

As described above, pharmaceutically active substances that are the subject of the present invention may also be present in the form of pharmaceutically acceptable salts, such as acidic/anionic or basic/cationic salts. Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzolsulfonat, benzoate, bicarbonate, bitartrate, bromide, edetate calcium, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, hydrabad�n, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesilate, methyl bromide, methyl nitrate, methylsulfate, mukata, napsylate, nitrate, pamoate, Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannat, tartrate, teoclate, tosylate and triethiodide. Pharmaceutically acceptable basic/cationic salts include, among others, salts of aluminum, benzatin, calcium, chloroprocaine, choline, diethanolamine, Ethylenediamine, lithium, magnesium, meglumine, potassium, procaine, sodium and zinc.

As described above, pharmaceutically active substances that are the subject of the present invention may also be present in the form of a prodrug pharmaceutically active substances. Typically, such prodrugs are functional derivatives of pharmaceutically active substances, which are easily convertedin vivoin the corresponding pharmaceutically active substance. Conventional procedures for the selection and obtaining of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. In addition to the salts of the present application for the invention involves the use of esters, amides, and other protected or derivatives of the described compounds.

In cases where the pharmaceutically active substance in accordance with �aseason invention have at least one chiral center, they may accordingly exist as enantiomers. In cases where the pharmaceutically active substances possess two or more chiral centers, they may additionally exist as diastereomers. You need to understand that all such isomers and mixtures thereof fall within the scope of the present invention. Moreover, some of the crystalline forms of pharmaceutically active substances can exist as polymorphs, which are supposed to also cover the present invention. In addition to the above, some of pharmaceutically active compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates also on the cover of the present invention.

In one example of the invention, the pharmaceutically active substance (or substances) present in the tablet in a therapeutically effective amount which represents the amount that causes a desired therapeutic effect when administered orally, and can be easily determined by a person skilled in the art. As is well known to experts in determining such amounts must be taken into account administered pharmaceutically active substance, its characteristics bioavailability, dosing regimen, the age and weight of the patient�, and also other factors.

Pharmaceutically active substance can be represented in various forms. For example, the pharmaceutically active substance may be dispersed at the molecular level, e.g. melted inside the tablet, or may be in the form of particles which, in turn, can be coated or not coated. If the pharmaceutically active substance presented in the form of particles (coated or not coated), how a rule, the average particle size ranges from about 1 to about 2000 microns. In one of the embodiments of the invention, such particles are crystals with an average particle size of from about 1 to about 300 microns. In another embodiment, the particles are granules or pellets with an average particle size of from about 50 to about 2000 microns, for example, from about 50 to about 1000 microns or from about 100 to about 800 microns.

Before applying masking the taste of the shell pharmaceutically active substance may be pure crystalline or granular form. Technology of pelletizing can be used to improve the flowability characteristics or size of the particles of pharmaceutically active substances for oble�cance of his subsequent pressing or coating the shell. Acceptable binder used in granulation technology include, among others, starch, polyvinylpyrrolidone, polymethacrylates, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Particles comprising a pharmaceutically active(s) substance(s) can be obtained by using joint granulating a pharmaceutically active(s) substance (substances) with the particles of the substrate using any known granulation method. Examples of such granulation method include wet granulation with large shear effort and granulation in a fluidized bed, for example, rotary granulation in a fluidized bed.

If the pharmaceutically active substance has an unpleasant taste, it is known to specialists, is a pharmaceutically active substance can be coated masking the taste of the shell. Examples of appropriate masking the taste of the membranes described in U.S. patent No. 4851226, in U.S. patent No. 5075114 and in U.S. patent No. 5489436. You can also use products available on the market pharmaceutically active substances with masked taste. For example, acetaminophen particles encapsulated in a shell of ethyl cellulose or other polymers by means of coacervation can be used in the present invention. Encapsule�created by coacervation acetaminophen may be purchased in the company Eurand America, Inc. (the city of Vandalia, Ohio) or Circa Inc. (Dayton, Ohio).

In one embodiment of the tablet contains coated particles, providing modified release (i.e., particles containing at least one pharmaceutically active agent, which provides modified release of such substances). As used herein, the term "modified release" should be applied in relation to the revised release or dissolution of the active substance in a solvent environment, such as a liquid medium of the gastro-intestinal tract. Types of modified release include, among others, slow or delayed release. Usually tablets with modified release is made in order to make a pharmaceutically active substance available for a long period of time after they are received, thus reducing the frequency of reception in comparison with the reception of the same pharmaceutically active substance (substances) in the traditional tablet. Tablets with modified release also allow the use of combinations of active substances, in which the duration of one pharmaceutically active substance may differ from the duration of another pharmaceutical� active substances. In one of the embodiments of the invention, the tablet contains one pharmaceutically active substance with the immediate-release and any additional active substance or the second part of the same active substances with modified release.

Examples of swellable licked hydrophilic materials for use as excipients which modify the release for use in modifying the release of the shell, include swelling in water cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene, acrylic polymers, hydrocolloids, clays and gelling starches. Examples of swellable in water of cellulose derivatives include nutricosmetics, cross-linked hydroxypropyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyisopropyl, hydroxymethylcellulose, hydroxyphenylethyl, hydroxyethyl cellulose (HEC), hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose. Examples of polyalkylene glycols include polyethylene glycol. Examples of acceptable thermoplastic polyalkyleneglycol include polyethylene oxide. Examples of acrylic polymers include the copolymer of potassium and methacrylaldehyde, �polimetilmetakrilat, as well as the homopolymers and copolymers with high molecular weight crosslinked acrylic acid.

Acceptable pH-dependent polymers for use as modifying the release excipients in modifying the release of the shell include enteric cellulose derivatives, such as phthalate of hydroxypropylmethylcellulose, acetate-succinate of hydroxypropylmethylcellulose, acetate-cellulose phthalate; natural resins such as shellac and Zein; enteric acetylpromazine, such as polyvinyl acetate phthalate, acetate-phthalate cellulose acetate acetylcholineesterase enteric greatperson, for example polymers based polymethacrylate, such as poly(methacrylic acid, methyl methacrylate) 1:2 (supplied by the company Rohm Pharma GmbH under the trademark EUDRAGIT S) and poly(methacrylic acid, methylmethacrylate) 1:1 (supplied by the company Rohm Pharma GmbH under the trademark EUDRAGIT L).

In one embodiment the pharmaceutically active substance is coated with a combination of water-soluble and film forming polymer (such as, inter alia, cellulose acetate or ethylcellulose) and water-soluble polymer (such as, inter alia, povidone, poly (methacrylic copolymers, supplied by Rohm America trading under the name�against Eudragit E-100, and hydroxypropyl cellulose). In this embodiment, the ratio of insoluble in water and forming a polymer film with water-soluble polymer is from about 50 to about 95% water-insoluble polymer and from about 5 to about 50% water soluble polymer, the weight ratio of the particles, coated with taste masking shell is from about 5 to about 40%. In one embodiment of the coating used in the coating having the particle of pharmaceutically active substances, essentially does not contain a material with a melting point below 85°C (for example, polyethylene glycol) to avoid compromising the integrity of the coating on the phase of the RF-heating.

In one embodiment, one or more pharmaceutically active substances or part of the pharmaceutically active substance may be associated with ion-exchange resin for taste masking pharmaceutically active agents or delivery of the active substance by means of modified release.

In one embodiment the pharmaceutically active substance can dissolve when coming into contact with the liquid medium, such as water, acid gastric juice, intestinal juice, etc. In one embodiment, the invention features�and the solubility of the pharmaceutically active substance, part of the tablets conform to the specifications of United States Pharmacopoeia (USP) tablet containing a pharmaceutically active ingredient immediate-release. For example, for acetaminophen tablets in USP 24 specifies that in phosphate buffer with a pH of 5.8 when using the device USP 2 (with paddles) at 50 rpm, at least 80% of the acetaminophen contained in the tablet is released within 30 minutes after ingestion, and for ibuprofen tablets in USP 24 specifies that in phosphate buffer with a pH of 7.2 when using the device USP 2 (with paddles) at 50 rpm, at least 80% of the ibuprofen contained in the tablet, released from it within 60 minutes after ingestion. Cm. USP 24, 2000 Version: 19-20 and 856 (1999). In another embodiment, the invention features the solubility of the pharmaceutically active substance is modified - for example, monitored, maintained, extended, slow, prolonged, delayed, etc.

In one embodiment, the implementation size of the particles of the pharmaceutically active substance promotes the formation of more voids in the tablet, while for particles of pharmaceutically active substances are larger in size, therefore requiring less water-containing material. In one embodiment, the implementation of the average particle size of the carbohydrate is more than 100 microns, pharmaceutical�and active substance or pharmaceutically active(s) substance(a) is coated(s) more than 50% of the weight. blend powder/tablets and the content of water-containing material is from about 2% to about 30% by weight. blend powder/tablets. In one embodiment, the implementation in which the average particle size of the powder mixture is from about 100 to about 300 microns, the content of water-containing material is from about 2% to about 15% by weight. powdered/tablet.

The melting point of the pharmaceutically active substance can affect the temperature on the heating stage, and also on the type of water-containing material. In one embodiment, the implementation of the temperature of dehydration of water-containing material is less than the melting temperature of pharmaceutically active substances. In another embodiment, the implementation of the melting point of the pharmaceutically active substance is equal to or below the temperature of dehydration of water-containing material. In one embodiment of the heating temperature exceeds the temperature of dehydration and melting of hydrous material, but does not reach the melting temperature of pharmaceutically active substances. In one embodiment, the implementation, where the pharmaceutically active ingredient is ibuprofen, a water-containing material is heated to a temperature from about 30°C to about 60°C. In one variant� the implementation of the pharmaceutically active agent is a binder material, water-reactive.

In one embodiment, the implementation of the pharmaceutically active substance is in the form of particles covered with the binder material, water-reactive.

The sensitivity of the pharmaceutically active substance to RF radiation (e.g., melting or destruction) may have an impact on the type of radiation and (or) temperature heating stage, and also on the type of slurry used for the connection.

In one embodiment, the implementation of technological treatment pills does not include the step of wet granulating or pelletizing of the melt. In this embodiment, the implementation of the materials are mixed directly before heating. In one embodiment, the implementation of the materials are mixed and pressed immediately before heating.

Getting the pill form

In one embodiment of the powder mixture is fed into a tablet press-shaped device, and attached to it a pressure for the formation of the preformed shape (for example, by a weak line, such as a rammer). For this you can use any appropriate device line, including, among other things, conventional one-piece or rotary tablet press. In one embodiment of the present invention, the preformed shape can be obtained by pressing with the help of ro�make sure the tablet press (e.g., press production Fette America Inc., (Rockaway, NJ) or Also Machines LTD (Liverpool, UK)). In one embodiment, the implementation of the preformed mold is heated after removal from the tablet press. In another embodiment of the preformed shape is heated inside the tablet press.

In one embodiment of the implementation to obtain the desired characteristics of the lozenges in the mouth of her design can be highly porous with a minimum quantity of binder and (or) low density. As a result of these pills turn out to be fragile and soft. In a preferred embodiment of implementation, to achieve dissolution of the tablet in the oral cavity (low density), it is desirable to use the minimum force of the ramming/pressing. The results of the experiments showed that during the compression of low load without the use of RF emissions are very fragile tablets, not withstanding the loads during the handling of material during the manufacturing process.

In most thermodynamic processes or devices of the heat source and heat removal are separate devices or stages, it is necessary to transfer the material from one device to another. In the process of manufacture of tablets comprising�, the subject of the present invention, to obtain the binding effect it is necessary to bring the tablet to power and then to lead them away from the product for its curing and acquire the strength necessary for manipulations related to packaging and use. One of the unique and unexpected properties of one embodiment of the production process constituting the subject of the present invention is that the heat source and the heat sink is part of a single device. In fact, in early experiments a metal forming device (for example, the punch of the mold), warmed to room temperature, brought so much warmth from being processed preformed shape (due to the high thermal conductivity) that the surface of the manufactured tablets was unacceptable due to uneven melting of the powder mixture. Made the tablet had a well-formed core, but on the surface was present in the free state is poorly molded powder that had no connection with the rest of the tablet. To eliminate heat losses in one embodiment of the molding device failed heating for proper sintering on the surface and in the center of the tablet.

To use this unique thermal effect can also pick up a powder mixture with defined thermal properties thermal conductivity and specific heat, to make the particles of the powder mixture were used as heat sinks. In a typical composition of tablets for dissolution in the oral cavity binder can be less than 10% of the mixture. The remaining 90% of the materials serve as a heat sink and quickly dissipate heat after turning off the radiation source (e.g., RF energy) as a result it is desirable that the total time of the technological process could be only a few seconds, and to eliminate the necessity of carrying pills with plates of the mold during the critical process of compacting and heating. Consequently, the plate of the mold can work as a device for material processing, as well as a thermoforming device. This is particularly beneficial from the point of view of the successful production of fragile tablets for dissolution in the oral cavity.

In one embodiment, the implementation stage of compression (e.g. tamping) before applying radiation (e.g., RF energy) apply less pressing load for pressing chewable tablets or tablets for ingestion. In one embodiment of the load during compaction is less than approximately 6,895 MPa (1000 psi) (for example, less than approximately 3,45 MPa (500 psi), for example, less of 1.38 MPa (200 psi), for example, less than 0.34 MPa (50-lb)). In about�nom embodiment of the irradiation is used, when the powder mixture is under a specified load.

In one embodiment, the implementation stage of pressing is discretely while pressing one of a set of tablets, after which there is a transition to another unit of the rotary table. In one embodiment, the implementation stage of compression takes place on one block, rotary table, and the use of radiation (e.g., RF energy) is performed on another block of the rotary table. In another embodiment, the implementation provided a third block, rotary table, in which the ejection of one or a plurality of tablets, wherein the lower molding device rises through the mold to the surface. In another embodiment, the implementation for pressing the top of the upper molding devices add a pneumatic or hydraulic cylinder. In one embodiment, the implementation of a lot of pills pushed at the same time or separately from the surface of the block, rotary table, and delete removes the rail.

In another embodiment of the preformed shape can be obtained by using the methods and devices of the line described in the publication of the patent application U.S. No. 20040156902. In particular, for the manufacture of tablets using a rotary press module having the area of filling, delivery, extruded�I, release and clearance in a single device with a double row arrangement of molds. Then the mold pressure module can be filled under vacuum. Next to each mold or set inside the filter. Area pressure cleaning module includes an optional system for the regeneration of powdered mixture that removes the excess powder mixture of filters and returns it to the mold. In one embodiment, the implementation of a radiation source (e.g., source of RF radiation) passes through a stamping table rotary press in the corresponding electrode in the molding or forming device cavity. In one embodiment of the stamping table is made of non-conductive material.

In another embodiment of the present invention, the portion of the preformed shape may be performed by the method of wet granulation, which involves mixing and granulation excipients and wet binder in solution or dispersed form (e.g. starch paste, water-based or solution of polyvinylpyrrolidone). A suitable device for wet granulation includes a mixer with low shear forces (for example, planetary mixers), a stirrer with large shear effort and fluidized layers (num� rotary fluidized layers). The obtained granulated material can be dried, and optionally dry-blended with further ingredients (e.g., adjuvants such as water-containing compound described in the present invention, lubricants, dyes, etc.). Then, the resulting dry mixture can be used for molding described in this document, ways. Methods direct compression and wet granulation known to specialists in this field.

In one embodiment of the preformed shape is obtained with the use of methods and devices for pressing, is described in published U.S. patent No. 6767200. In particular, to form tablets using a rotary press module having the area of filling, pressing and pushing in the same device with a double row arrangement of molds, as shown in FIG. 6 of this document. The mold pressure module preferably filled under vacuum. Next to each mold or set inside the filter.

Tablet form may have one of many different forms. For example, the preformed shape can be made in the form of a polyhedron such as a cube, pyramid, prism, etc., or may have the geometry of three-dimensional shapes with non-planar surfaces, such �AK cone, truncated cone, triangle, cylinder, sphere, torus, etc. In some embodiments, the preformed shape has one or more large faces. For example, the surface of the preformed shape, usually has opposite upper and lower sides formed in contact with upper and lower surfaces of the molding device (for example, the punches of the mold in the compactor. In such embodiments, the surface of the preformed shape usually has a "belt" located between the upper and lower sides and is made in contact with the walls of the mold in the compactor. Tablet form or tablet can also be layered. The applicants have found that the sharp edges of the device used for the manufacture of tablets may contribute to the formation of arcs. Therefore, more rounded edges may be the preferred option.

In one embodiment of the method of producing pelletized form essentially involves the use of solvents. In this embodiment of the powder mixture essentially contains no solvents, and the production process (for example, the process of filling molds) is also essentially linked to the use of solvents. To solvents can Rel�agree, among other things, water, organic solvent, such as, inter alia, alcohols, chlorinated solvents, hexane or acetone; or gaseous solvent, such as, inter alia, nitrogen, carbon dioxide or supercritical fluid.

In one embodiment, the implementation applies the phase of vibration exposure (e.g., added after the introduction of the powder mixture, but before the heating or melting, to remove air from the powder mixture). In one embodiment, the implementation uses a vibration with a frequency of about 1 Hz to about 50 kHz and mezhpolovoe amplitude from 1 micron to 5 mm, which contributes to the stabilization of the flow of the powder mixture in the cavity plate of the mold (molding cavity).

In one embodiment of the implementation, as shown in FIG. 1A-1F, a measured volume of powder blend 4 is poured into a plate mold 2 made of Teflon (or similar material having insulating properties against electric current and RF radiation, for example, ceramics or ultracytochemical plastic). Plate of the mold 2 has a moulding cavity 5 with the inner wall 6, the upper opening 7 on the upper surface plate of the mold 2 (through which the powder mixture 4 and the upper moulding unit 1 is fixed in the molding cavity 5), the lower hole 8 on protivopul�l of the plate surface of the mold 2 (through which the powder mixture 4 and the lower molding device 3 included in the moulding cavity 5). The powder mixture may 4 under the action of gravity or mechanically fed from a dispenser (not shown). Metal conductive bottom forming device 3 includes a plate in the mold and holds the powder mixture 4 in the plate of the mold 2. Similar conductive metal of the upper moulding unit 1 is located above the plate of the mold 2, as shown in FIG. 1B. Then the molding device 1 and 3 plate mold 2, and the powder blend 4 is moved to the pressing unit and RF heating, as shown in FIG. 1C, to form a tableted form 4a.

This heating unit is an RF generator 7 that generates a high voltage, high frequency radiation. Generator 7 has an electrical connection with a movable upper RF electrode plate 8 and the movable bottom RF electrode plate 6. As shown in FIG. 1C, in this position the powder mixture 4 are pressed between the upper mold 1 and lower mold device 3 by means of pressure exerted upper RF electrode plate 8 and the lower electrode plate 6, with the formation of the preformed shape 4a. Then tableted form 4a is exposed to RF energy using an RF generator 7, heating the water-containing compound in tablet form 4a. Last� off RF radiation tablet form 4a cools, forming a tablet 4b. In one embodiment, the implementation shown in FIG. 1D, 4b tablet push out the top of the molding device 1 from the plate of the mold 2 into blister 8, which is used for packing tablet 4b. In the alternative implementation shown in FIG. 1E, 4b tablet is pushed from the plate of the mold 2 of the lower molding device 3 and fed to a discharge tray removable stationary rack (not shown). FIG. 1F presents a three-dimensional image forming devices 1 and 4, plate of the mold 2 and 4b pills.

FIG. 2A-2H presents an alternative embodiment of the invention, which shows a method of manufacturing a multilayer tablet. First poured the powder mixture 10 in the plate of the mold 2, as shown in FIG. 2A. The powder mixture 10 RAM or move deep into the plate of the mold 2 through the top of the molding device 1, as shown in FIG. 2B, to form a preformed shape 10a. Then on top of the pill form 10A poured the powder mixture 11. After that, the molding device 1 and 3 plate mold 2, the tablet form 10A and the powder mixture 11 is moved to the pressing unit and RF heating, as shown in FIG. 2E. RF heating is produced as described above in FIG. 1C, and is made of a multilayer tablet 12, as shown in FIG. 2F and 2G. Although the figure showing�on a two-layer tablet, you can enter multiple additional layers by adding additional powder mixture on the plate of the mold 2.

FIG. 3A-3G presents another variant implementation of the invention, in which in pill form 20A is injected preformed inserts 30 and 31, as shown in FIG. 3A-3D. Then the molding device 1 and 3 plate mold 2, the tablet form 20 and preformed inserts 30 and 31 is moved in the pressing unit and RF heating, as shown in FIG. 3E. RF heating is produced as described above in FIG. 1C, and is made of multi-component tablet 40, as shown in FIG. 2F and 2G.

FIG. 4A and 4B shows two images of the machine with rotary indexing table 195 developed for the production of large quantities of tablets. In particular, the device is made with the possibility of production of fragile tablets with minimal risk of damage during the manufacturing process. This variant implementation of the present invention includes the index table 170 having four sets of plates molds 175 with sixteen holes in each of the powder dispenser 100, RF generator 150, the machine frame 140, the mobile node RF electrodes 120 and 130, the lower the moulding unit 110, the upper molding the node 210, the block popping pills 160, a drive system dividing unit 180, blister�e packing blade 190 and the roll of material for sealing blisters 191.

Fig. 5A presents a top view of the device in stop position. Fig. 5B presents a top view of the device at the moment when the index table 170 rotates between the blocks in the direction A. In Fig. 6A shows a view in section of the lower moulding of the node 110 in a position corresponding to the beginning of the production cycle. The lower forming device 111 is made of conductive metal material such as brass or stainless steel, is fixed in the base plate 112 (made of, e.g., aluminum or steel). The heating unit 117 is attached to the base plate 112 and contains channels for the liquid medium 117b. Circulation of the heating (or optional cooling) of the fluid in the heating unit 117 provide a through connection with flexible hoses 119a and 119b, which form a line inlet and outlet. Heating can also be carried out using cartridge heaters or other appropriate means (not shown). To the base plate is attached to the support roller 114 and linear bearing 113. By dividing the table 170 is attached to guide shaft 116. Base plate and forming device 111 can be moved up or down in accordance with the profile of the drum Cam 115, which travels the length of the support roller 114. Also shown is plate PR�SS-form 171, made of electrical and RF insulating material, such as Teflon, ultracytochemical ceramic or plastic. This is to prevent short circuit in case of placement of conductive molding devices in a radio-frequency electric field at a later stage. Molding cavity 171a at this stage of the technological process is shown empty.

Fig. 6B shows a cross section of the block of powder dispenser device 100. In this block powder blend 101 under the action of gravity is supplied to the plate of the mold 171. By raising or lowering the movable Cam segment 118 in the direction B to adjust the volume of the molding cavity 171a, changing the distance that the bottom of the molding device 111 included in the plate of the mold 171. Such adjustable volume allows you to select the exact dose of the powder mixture for the manufacture of tablets of the desired weight. When dividing the table moves away from the block of powder dispenser, an edge of the dispenser 102 scrapes the powder from the plate of the mold 171, forming a flat surface relative to the surface plate of the mold 171.

Fig. 7 presents a sectional view of the block RF interference. RF generator 150 in this figure is shown symbolically. In one embodiment of the RF generator 150 is a generators� free oscillations. Typically, it consists of a powerful vacuum tubes (e.g. triode) and source DC power from 1000 to 8000 volts, is connected between cathode and plate (anode). The resonant circuit takes the sinusoidal signal to the control grid and the electrodes, resulting in the generated high-voltage field for the desired frequency (typically 13.56 MHz to 27.12 MHz). An example of such RF generator 150 is the generator of a COSMOS model C10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, new York). In another embodiment of the RF radiation produced by the system impedance of 50 Ohms, consisting of a generator of oscillations of a given shape, feeding the RF signal to the power amplifiers connected to the electrodes, and load in the form of circuit impedance matching.

Fig. 7 shows the lower movable RF electrode 121, is arranged to move in the direction D. In the figure it is shown in the lower position. Linear motion carried by the linear actuator, which is typically provided by pneumatic cylinders or servomotors. Fig. 7 shows two pneumatic cylinders. Housing cylinders 141 and 142 are putting pressure on guide rods 144 and 143. To the guiding rods attached to the moving plate 132 and 122, which can be isolated from the electricity mount electric�derivative plates 131 and 121. RF generator 150 is connected to the electrode plates 131 and 121 through the wires 185 and 184. Moving the top node of the RF electrode 130, is arranged to move in the direction C shown in the upper position. Top of the molding device 133, the base plate 134 and the heating block 135 is attached to the movable RF electrode plate 131 and, therefore, moving with her up and down. A powder blend 101 is in the plate of the mold 171.

Fig. 8 shows a sectional view of the same block RF radiation, but the RF electrodes 131 and 121 shown opposite the respective molding nodes 133 and 111 for pressing and RF irradiation of the powder mixture 101 for the formation of tablets 101a. After the termination of RF-irradiation is removed, the movable RF electrode plate and move the dividing plate 170, the plate of the mold 171 and bottom of the moulding unit 110 on the next block.

Fig. 9 shows a sectional view of the block popping pills to 160. Ejector pins 161 are attached to the movable plate 162 (movable in the direction E) set in motion a drive node 163 (which may be, for example, a linear actuator, a pneumatic cylinder or other suitable actuator). The drive rod 166 is connected to the movable plate 162. Linear bearing 164 and guide rod 165 impart rigidity and the prop drive plate 162 and prevent� destructive lateral loads, are generated by the ejector action of the actuator 163. Under the plate of the mold 171 shows a blister package 190.

Fig. 10 shows a sectional view of the same site after pushing ready tablets 101a with the help of ejector pins 161 through the plate of the mold 171. Direct penetration of tablets in blister avoids the destruction of the tablets, the probability of which exist when using traditional methods, such as the supply or discharge of the tablets in conveying capacity.

In one embodiment, the implementation before the introduction of the granular powder mixture in the molding cavity add lubricant. Lubricant may be liquid or solid. Acceptable lubricants include solid lubricants such as magnesium stearate, starch, calcium stearate, aluminum stearate and stearic acid; or liquid lubricants, including, but not limited to, simethicone, lecithin, vegetable, olive or mineral oil. In some embodiments, a lubricant is added in a percentage ratio to the weight of the tablet is less than 5%, e.g., less than 2% or, for example, less than 0.5%. In some embodiments, the presence of a hydrophobic lubricating agent may be adverse and lead to poor resorption or dissolving�in termination of the pill. In one embodiment of the tablet essentially does not contain a hydrophobic lubricant. To hydrophobic lubricating agents include magnesium stearate, calcium stearate and aluminum stearate.

Heating the preformed shape with the formation of tablets

In a process for heating a water-containing compounds can be used various forms of radiation. Permitted sources of radiation include, including, convection, radio frequency radiation, microwave radiation, UV radiation, infrared, induction, laser radiation and ultrasound. In one embodiment, the implementation uses radio frequency radiation. Radio-frequency heating, commonly referred to as heating by an electromagnetic field with a frequency of approximately 1 MHz to approximately 100 MHz. In one embodiment of the present invention, RF radiation has a frequency in the range from approximately 1 MHz to approximately 100 MHz (e.g., from approximately 5 MHz to 50 MHz, for example, from approximately 10 MHz to approximately 30 MHz). Generators of RF radiation are well known to those skilled in the art. Examples of valid RF generators include, among other things, the generator COSMOS model C10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, new York).

Radiation (e.g., RF�zlecenie) use for heating water-containing compounds. The hardness and / or type of pills (oral-disintegrating tablet in the oral cavity or soft chewable tablet) may depend on the degree of compaction, the type and number of water-containing compounds and the amount of radiation.

In one embodiment, the implementation in the application of RF energy top and bottom of the molding device are the electrodes (for example, they are connected to a source of RF energy in working condition), through which is used to supply RF energy to the tablet form. In one embodiment, the implementation of direct contact between at least one RF electrode (e.g., forming the device) and tableted form. In another embodiment, the implementation is not provided for direct contact between at least one RF electrode (e.g., forming the device) and tableted form. In one embodiment of the RF electrodes in direct contact with the surface of the preformed shape in the process of RF exposure. In another embodiment of the RF electrodes are not in contact (e.g., located at a distance of from approximately 1 mm to approximately 1 cm from the surface of the preformed shape) in the process of RF exposure.

In one embodiment of the RF radiation used in forming preformed shape. In one embodiment �of sushestvennee RF radiation is applied after formation of the preformed shape. In one embodiment of the RF radiation is used after the extraction of the tablets from the mold.

In one embodiment of the RF radiation used for a period of time sufficient for heating essentially all (e.g., at least 90%, e.g. at least 95%, e.g., all) of the water-containing material specified in tablet form to a temperature above its temperature of dehydration. In one embodiment of the RF radiation used for a period of time sufficient to heat only portions (e.g., less than 75%, e.g., less than 50%, e.g., less than 25%) of the water-containing material in form of tablets, for example, on only one plot preformed shape, for example, outside the pill form.

In alternative embodiments, the molding device can be performed with the possibility of localized heating, and can also be configured to impart a specific shape to the electric field generated between devices. Fig. 11A presents one of such configurations. RF generator 200 is connected to the plates of the RF electrodes 201 and 202. The molding device 205 and 204 made of conductive material and have pads 207 and 208 made of electrical and RF insulating material such as ceramic, Teflon, Paul�ethylene and high density polyethylene. Plate of the mold 203 is also made of electrical and RF insulating material. This configuration allows you to create a greater distance between the conductive molding devices for weakening the electric field that is preferred for the manufacture of thin pills without the risk of formation of an electric arc, which may damage the product and equipment. Fig. 11B shows a similar configuration, but with the forming devices 210 and 211 having, respectively, grooves with inserts 213 and 212 made of electrical and RF insulating material. With this geometry in the manufacturing process of tablets in the area of inserts 213 and 212 of the heating will be less, since the electric field is weakened due to the increase of the distance between conductive zones 211 and 210. Fig. 11C is similar to Fig. 11B, only the geometry in this case is reversed, and the production of tablets, the heating will be more in the Central part because of insert 216 and 217 are at the periphery of the corresponding molding devices 214 and 215. Fig. 11D presents another variant implementation, in which the plate of the mold is composed of an electrically conductive component 221 and the insulating component 222 and is made of electrical and RF insulating material. Moulder 219 and 218 are electrically conductive, but formulas�th device 218 further comprises a second insulating component 220, located around the upper surface of the molding device 218 that is in contact with a preformed shape 206. This configuration creates an electric field and corresponding heating zone, primarily related to conductive areas of the plate mold.

Fig. 12A is similar to Fig. 11D, except that the plate of the mold 233 in this embodiment, the implementation is completely made of conductive material. Fig. 12B and 12C are presented two variants of implementation, in which the plate of the mold contains a corresponding electrically conductive Central portion 245 and 254 and the corresponding outer part 244/246 and 252/253, made of electrical and RF insulating material. Fig. 12B further shows an insulating component 220 that is located around the lower surface of the molding device 219. Fig. 12D shows another variant implementation, in which the molding device 263 and 262 are made of electrical and RF insulating material. Plate parts of the mold 264 and 265 are made of electrical and RF insulation material, but two respective conductive parts 267 and 266 are connected to the circuit of the RF generator 200. In this configuration, the electric field acts in a horizontal direction across the pill form 206.

As indicated above, the distance between electropop�ceived parts of the molding device greatly affects the field strength and the heating effect. For the manufacture of tablets with a uniform warm-up and structure it is desirable that the molding devices were equidistant from each other. Fig. 13A and 13B presents this configuration. In this embodiment, the embodiment shown undulating moulder 270 and 273, which allows to form in the plate of the mold 271 tablet 272 unique look. The profiles of the surfaces of the molding device are equidistant from each other by a distance X.

Fig. 14 shows a variant implementation, in which for the manufacture of tablets 282 apply uneven heating. In this embodiment, the implementation is made tablet with hard and soft zones. Moulder 280 and 281 are made with protrusions on the surface, creating a field of high intensity (and more heat) where they are closer to each other (distance Z), and field a weaker tension (and less heat) where they are further away from each other (distance Y).

In one embodiment, the implementation to reduce the stickiness tablet cool inside the moulding cavity to the cooling and / or solidification of the binder. Cooling can be passive (for example, at room temperature) or active (for example, by means of circulating coolant). When using cooling using the circulating cooling�promoting substances the coolant may not necessarily circulate through the channels in the molding devices (such as punches or plate of the punch) and / or the mold or plate mold (e.g., as described above in FIG. 6A and 6B). In one embodiment, the implementation in the technological process using a plate mold having a plurality of cavities, and the upper and lower plate of the punch having a plurality of upper and lower punches for the simultaneous molding of a plurality of tablets, wherein the plate is actively cooled.

In one embodiment, the implementation includes one powder mixture, from which the preformed form, which is then heated under the action of RF radiation. In another embodiment of the tablet is made of at least two powder mixtures, wherein at least one of the powder mixture is cured under the action of RF radiation, and at least one composition is not cured under the action of RF radiation. In the process of curing under the action of RF energy in this tablet form form two or more zones with different degree of cure. In one embodiment of the peripheral region of the preformed shape is cured, and the Central region of the preformed shape is not cured. The change in center of RF heating and shape of the RF electrodes contributes to the concentration of heat on�led to pill form to create a softer or firmer areas in the finished tablet.

In one embodiment of the RF radiation is combined with a second heat source, including, without limitation, infrared, induction or convection heating. In one embodiment, the implementation of the introduction of the second heat source is particularly relevant if the powder mixture is present secondary, not melts the RF radiation of the binder.

In one embodiment of the powder mixture is sealed inside the chamber during the step of irradiation to ensure the localization and distribution of water in the powder mixture. In one embodiment, the implementation of such a sealed chamber consists of a mold and at least one heat source (e.g., RF electrode). In one embodiment, the implementation at the opening of the sealed chamber molten pill subsequently dried to remove water. Drying can be carried out using the specified source of radiation or other source of heat.

In one embodiment, the implementation in the production of tablets using microwave radiation (for example, instead of radio-frequency radiation). Microwave heating as a rule, is called the heating electromagnetic field with a frequency of approximately 100 MHz to approximately 300 GHz. In one embodiment, be implemented thr�of the present invention, the microwave radiation is in the range of frequencies from about 500 MHz to about 100 GHz (for example, from approximately 1 GHz to 50 GHz, for example, from approximately 1 GHz to approximately 10 GHz). Microwave radiation is used to heat the water-containing material. In this embodiment, the implementation in the device used for the manufacture of tablets, using a source of microwave radiation and microwave electrodes.

Insert into pill form

In one embodiment, the implementation before irradiation in pill form, injected insert. Examples can be solid extruded shapes or balls with a liquid content. The introduction of such insert is shown in Fig. 3A-3G.

In one embodiment, the implementation of the pharmaceutically active substance has the form of a gel bead with liquid or semi-liquid filling. Gel(s) bulb(s) is introduced into the powder mixture. In one embodiment of the tablet constituting the subject of the present invention, has the following additional property: if its production does not use the strong stage of pressing, which allows the use of deformable particles or beads with liquid or semi-liquid filling, because the use of lower pressure they will not be torn at the stage of pressing. The walls of such balls may contain gelling agents such as gelatin, Galanova gum, xanthan gum, agar, gum beans carob�on wood, carrageenan, polymers or polysaccharides, including, without limitation, sodium alginate, calcium alginate, hypromellose, hydroxypropyl cellulose and pullulan, polyethylene oxide, and starch. Wall balls can further contain a plasticizer, e.g., glycerol, polyethylene glycol, propylene glycol, triacetin, triethylcitrate and tributyltin. Pharmacologically active substance can be dissolved, suspended or dispersed in the filler material, for example, among other things, in the corn syrup with high fructose, sugars, glycerin, polyethylene glycol, propylene glycol, or oils, such as, inter alia, in vegetable, olive or mineral oil.

In one embodiment, the implementation in the application of RF energy box essentially does not contain ingredients that absorb RF radiation, and in this case, the application of RF radiation does not significantly heat the insert. In other embodiments, the insert contains ingredients that the heating under the action of RF radiation, and, therefore, such inserts can be used to soften or melt the water-containing material and (or) fusible binder.

Multilayer tablet

In some embodiments, the tablet includes at least two layers, for example, with time�bubbled types and / or concentrations of water-containing material and / or other ingredients or different concentrations of pharmaceutically active substances. This variant of the implementation shown in FIG. 2A-2D. In one embodiment of the tablet contains two layers, one of which dissolves in the mouth, and the other is intended for chewing or swallowing. In one embodiment, the implementation of one layer comprises a water-containing material and the other layer contains a water-containing material. In one embodiment, the implementation of one layer are pressed at a higher pressure than the other layer. In one embodiment, the implementation of both layers contain the same amount of water-containing material, but different amounts of pharmaceutically active substances and / or other excipients. In one embodiment, the implementation of all the properties of the two layers are identical, except that they have different color.

Effervescent couple

In one embodiment of the powder blend further comprises one or more effervescent couples. In one embodiment of the effervescent couple contains one substance from the group consisting of sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate and sodium carbonate, and one substance selected from the group consisting of citric acid, Accenture acid, fumaric acid, tartaric acid, phosphoric acid and alginic acid.

In one embodiment, the overall content of effervescent () pairs (p�p) in the powder mixture or the tablet is from about 2 to about 20% by weight., for example, from about 2 to about 10% by weight. of the total weight of the powder mixture or tablets.

Oral-disintegrating tablet in the oral cavity

In one embodiment the tablet is capable of resorption in the oral cavity in less than about 60 seconds after placing it on the tongue, for example, less than about 45 seconds, e.g., less than about 30 seconds, e.g., less than about 15 seconds.

In one embodiment of the tablet meets the requirements to tablets for dissolution in the oral cavity, as defined in the draft guidance FDA food and drugs, published in April 2007. In one embodiment of the tablet corresponds to the double definition of tablets for dissolution in the oral cavity, including the following criteria: 1) solid tablet contains a drug rapidly dissolves when placed on the tongue, usually within a few seconds, 2) can be considered as a solid dosage form for oral administration, which rapidly dissolves in the oral cavity, the time of resorption in vitro is approximately 30 seconds or less in the analysis by testing for resorption installed in farm�copey USA (USP) for a specific(s) of drug(s) drug(s).

Additional edible part

In one embodiment of the tablet is used with other edible dosage form. In one embodiment, the implementation of this edible dosage form is a caramel or extruded ring that holds the powder mixture at the stage of pressing and / or heating.

In one embodiment of the present invention, the outer shape of the caramel can be made with universal line for the production of caramel topping or caramel candy, comprising the sequential elongation of the caramel mass, its rolling, the subsequent cutting and stamping by special forms. Caramel part contains one or more sugars selected from the group consisting of isomalt, sucrose, dextrose, corn syrup, lactitol and lukasina. In one embodiment of the caramel portion contains at least 50% (e.g., at least 75%, e.g., at least 90%) weight. this(their) sugar(s).

In one embodiment of the outer edible form contains a pharmaceutically active substance, and inside tablet contains the second part of the same pharmaceutically active substance, and in the outer edible form. In one embodiment of the outer edible form contains f�rmaceutical active substance, and inside the tablet contains a different pharmaceutically active material than in the outer edible form. In one embodiment of the outer edible form dissolves at least 10 times faster, for example at least 20 times faster than the inner tablet. The first and second parts may be the same or different.

In one embodiment of the tablet consisting of edible external shape and internal tablets, coated immediate release of sugar or film coating. In one embodiment, the implementation in the production of tablets phase after fusing (heating) and subsequent cooling of the tablet, must include the stage at which the tablet is covered with a film or sugar-coated with pan coating.

Hardness/density preformed shapes/pill

In one embodiment of the tablet is made in such a way that it is relatively soft (e.g., able to dissolve in the mouth or suvatsa). In one embodiment, the implementation of the hardness of the tablet is preferably less than approximately 29 N/cm2(3 thousand pounds per square inch (thousands of f/cm2)) (for example, less than approximately 20 (2 thousand f/cm2), for example, less than approximately 9.8 N/cm2(1 thousand f/cm2)).

In this area the term "hardness" refers to breaking load in the diametrical direction, as measured using conventional pharmaceutical hardness analyzers, for example, using the Schleuniger device. To compare values for tablets of various sizes need to be normalized failure load to the area of the fracture. This normalized value, expressed in N/cm2(in thousand f/cm2), sometimes this area is called the tensile strength of tablets. General description of the process of evaluating the hardness of the tablets can be found in the publication Leiberman et al., Pharmaceutical Dosage Forms-Tablets, Volume 2, 2.sup.nd ed., Marcel Dekker Inc., 1990, p. 213 to 217, 327-329.

Preferable to assess the hardness of the tablets that are the subject of the present invention based on the use of the texture analyzer TA-XT2i, equipped with a probe with a flat end face with a diameter of 7 millimeters and is configured to measure the force of compression and the formation of a report on the results in grams. The tip makes a motion at a rate of 0.05 mm / sec to a depth of 2 mm. Record the maximum value of the compressive force. In one embodiment, the implementation of the measured values of the force for tablets made in accordance with the present invention, amounted to less than 10,000 grams (for example, less than about 1000 grams, for example, less than about 700 grams). In one embodiment, osushestvlenie� measured values of the force for tablets, manufactured in accordance with the present invention were in the range of from about 100 to about 6000 grams, for example, from about 100 to about 1000 grams, for example, from about 75 to about 700 grams ±50 grams. In another embodiment of the measured values of the force for tablets was less than 700 grams.

In one embodiment, the implementation of the density of the tablet is less than about 2 g/CC (e.g., less than about 0.9 g/CC, for example, less than about 0.8 g/CC, for example, less than about 0.7 g/CC). In one embodiment, the implementation of the difference in density of the powder material after the extrusion was less than about 40 percent (e.g., less than about 25 percent, e.g., less than about 15 percent).

Coating tablets

In one embodiment of the tablet has an additional outer coating (e.g., a transparent cover such as a transparent coating) that reduce the fragility of the tablet. Acceptable materials for translucent coatings include, among others, hypromellose, hydroxypropyl cellulose, starch, polyvinyl alcohol, polyethylene glycol, mixtures and copolymers of polyvinyl alcohol and polyethylene glycol, and mixtures of these prophetic�TV. Tablets that are the subject of the present invention may contain a coating comprising from about 0.05 to about 10 percent, or from about 0.1 to about 3 percent of the total weight of the tablet.

Surface treatment pills

In one embodiment, the implementation of the surface tablets and / or tablets are further processed by applying energy (e.g., convection, infrared or RF exposure) to soften or melt the material on the surface of the tablet, and then cooled actively or passively, to make the texture more smooth, strengthen glossy sheen of the surface tablet, to reduce the brittleness of the tablet and (or) marking for identification. In one embodiment, the implementation of surface tablets were additionally irradiated with infrared rays, a large portion (at least 50%, e.g. at least 90%, for example at least 99 percent) of infrared radiation had a wavelength in the range from about 0.5 to about 5 micrometers, e.g., from about 0.8 to about 3.5 micrometers (for example, using a filter with a certain wavelength). In one embodiment, the implementation of a source of infrared radiation served to�arava lamp with a parabolic reflector (for example, for amplification of the radiation) and filter to remove unwanted frequencies. Examples of such energy sources is part of the SPOT device IR 4150 (produced by Research, Inc., city of Eden Prairie, Minnesota).

The use of pills

For the introduction of pharmaceutically active substances can be used swallowing, chewing tablets or lozenges in the mouth.

In one of the embodiments of the present invention, the claimed method of treatment of a pathological condition, namely, the method comprising oral administration of the above tablets, this tablet includes a dose of a pharmaceutically active substance that is effective for the treatment of this pathological condition. Examples of such conditions include, among other things, pain (e.g., headaches, migraines, sore throat, spasms, back pain and myalgia), fever, inflammation, pathological conditions of the upper respiratory tract (for example, cough and congestion), infections (such as bacterial and viral infections), depression, diabetes, obesity, pathology of the cardiovascular system (such conditions as high cholesterol levels, triglycerides and blood pressure), pathological conditions of the gastrointestinal tract (e.g., nausea, diarrhea, irritable bowel syndrome and increased� gas), sleep disorders, osteoporosis and nicotine addiction.

In one embodiment, the implementation of the described method of treatment of diseases of the upper respiratory tract, in which the pharmaceutically active substance selected from the group consisting of phenylephrine, cetirizine, loratidine, Fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine, chlophedianol and pseudoephedrine.

In this embodiment, the implementation of the "standard dose" as a rule, is accompanied by instructions on the dosage at which the patient is encouraged to take the pharmaceutically active substance in a quantity constituting a variety of standard doses, for example, depending on the age or weight of the patient. Typically, the pharmaceutically active substance is included in the scope of the standard dose in an amount sufficient to provide a therapeutic effect for the patient, satisfying the minimum parameters. So, a suitable volumes of standard dose can be a single tablet.

Examples

Some specific embodiments of the present invention are illustrated by the following examples. The present invention is not limited to the particular scope of these examples.

EXAMPLE 1

Preparation of powder mixtures containing acetaminophen

The powder mixture with acetaminophen for the manufacture of tablets for Russ�of syvania in the oral cavity, containing the ingredients shown in table 1, receive the following way:

Table 1
The composition of the powder mixture, covered with acetaminophen
Ingredientg/partymg tablet
Dextrose monohydrate6,14552,78
Maltodextrin0,654
Sucralose NF0,065,4
D&C yellow No. 10 Al Lake0,010,54
Coated acetaminophen (91%)*1,94174,78
Peppermint0,19
Sodium phosphate disubstituted as USP**0,7567,5
Polyethylene oxide NF0,436
10900
* Production company Eurand, city of Vidalia, Ohio.
** Na2HPO4·7H2O. by Dow Corporation, Midland, Michigan.

Each ingredient is sifted through a 30 mesh sieve, put all the ingredients together in a plastic bottle with a volume of 500 CC and stirred by rotation from the bottom to the lid for 5 minutes.

EXAMPLE 2

Production of oral disintegrating tablets in the oral cavity containing acetaminophen

Part of the powder mixture from example 1 was placed in a molding cavity (diameter 1.27 cm (1/2 inch)) plate mold made of Teflon (insulating material). Then the powder mixture was compacted between the upper and lower metal molding device with a flat end face, whereby it acquired a shape corresponding to the molding surfaces of the devices. The value of pressure when tamping, as a rule, were in the range of from 0,069 (10) to approximately 0,34 MPa (50 psi). After that, moulder, plate of the mold and the preformed shape is placed between the upper RF electrode and the lower RF electrode is connected to the heating RF module that contains an RF generator COSMOS model C10X16G4 (Cosmos Electronic Machin Corporation, G. Farmingdale, new York) with an output of 4 kW, a frequency of 27 MHz and a vacuum capacitor 140. Moulder was heated by circulating water at a temperature of 57°C. the Upper RF electrode is put in contact with the upper molding device, and the lower RF electrode is put in contact with bottom of the molding device. Heating RF module included for 2 to 5 seconds. Then made a tablet is pushed from the plate of the mold through the bottom of the molding device.

EXAMPLE 3

Obtaining edible external annular part with a molten inner part of the oral disintegrating tablets in oral cavity

(a) Obtaining edible external annular part

All materials listed below in table 2, manually sieved through a 30 mesh sieve. One and a half (1,5) kg of the resulting mixture was placed in a V-shaped mixer with a capacity of 4 quarts and stirred for 5 minutes.

Table 2
IngredientsWeight percent
by weight
Weight (mg)
Sorbitol550
Compressible sucrose* *92,75 927,5
Menthol110
Flavor peppermint0,55
Magnesium stearate0,757,5
TOTAL1001000
* Production company Domino Specialty Ingredients, Baltimore, Maryland.

Four hundred grams (400 g) of the mixture was removed from the mixer and subjected to compression processing using a rotary tablet press, when the rotation speed of 60 rpm with the use of 1.91 cm (3/4 inch) of the device for annular tablets to obtain a flat ring having an empty Central part of the size of ½ inch and a weight of 1000 mg, a hardness range of not less than 147 N/cm2(15 thousand pounds/cm2) and a thickness of about 0,508 cm (0,20 inch).

(b) Receiving the inner part of the oral disintegrating tablets in oral cavity

The powder mixture with loratadine immediate release for manufacturing tablets for dissolution in the oral cavity, containing the ingredients listed in table 3, was prepared as follows:

Table 3
Granulated mixtureg/partymg tablet
Dextrose monohydrate86,67433,3
The hydrate of sodium hydrophosphate9,6248,1
Sucralose USP0,63
Flavoring1,125,6
Loratadine210
Total100500

Dextrose monohydrate, the energy and flavor were sifted through a 30 mesh sieve, placed in a plastic bottle with a volume of 500 CC and stirred by rotation from the bottom to the lid for 5 minutes. Added loratadine and hydrate of sodium hydrophosphate and stirred by rotation from the bottom to the lid for another 3 minutes.

(c) Obtaining edible external annular part with a molten inner part of the oral disintegrating tablets in oral cavity

Received on this�e (b) the powder mixture is then removed from the mixer. Obtained in step (a) edible external annular parts separately placed in a molding cavity plate of the mold, as described in example 2. Next, the powder mixture obtained in step (b), was placed in the Central part of the annular parts and neatly stamped under the load of 45.4 kg (100 pounds) for receiving the dosage form with a total weight of 1500 mg. Further, the upper molding device was placed approximately 1 cm above the surface of the dosage form and activated the RF electrodes for a period of time from 2 to 5 seconds as described in example 2. Then made a tablet is pushed from the plate of the mold through the bottom of the molding device.

It is assumed that although the invention is described in detail, the above description is intended to illustrate and not limit the scope of use of the invention, which defines the area indicated in the attached claims. Other aspects, advantages and modifications are determined by these claims.

1. A method of manufacturing a tablet comprising stages, which compress the powder mixture in a plate mold for the formation of the preformed shape, the given powder blend contains a pharmaceutically active substance and hydrated sugar, and you provide during account creation affects�Yu tableted form of radiation over time, sufficient for heating the water-containing material specified in tablet form to a temperature above its temperature of dehydration for the formation of specified tablets.

2. A method according to claim 1, wherein said radiation is radio frequency radiation.

3. A method according to claim 1, wherein the specified powder blend further comprises one or more carbohydrates.

4. A method according to claim 1, wherein the specified powder mixture contains from about 0.01 to about 30 percent by weight of the specified pharmaceutically active substance and from about 1 to about 30 percent by weight of the specified water-containing material.

5. A method according to claim 3, in which the specified powder mixture contains from about 0.01 to about 30 percent by weight of the specified pharmaceutically active substance, from about 1 to about 30 percent by weight of the specified water-containing material and from about 30 to about 95 percent by weight of the specified one or more carbohydrates.

6. A method according to claim 1, wherein said water-containing material is a hydrated salt.

7. A method according to claim 3, in which the specified one or more carbohydrates selected from the group consisting of dextrose monohydrate, mannitol, eritria, dextrose, lactose, sorbitol, isomalt, sugar�roses, dextrates and maltodextrins.

8. A method according to claim 1, wherein said radio-frequency radiation applied to said preformed shape in said plate molds.

9. A method according to claim 1, wherein the specified powder mixture is pressed with a force of less than 0.3 kilonewton.

10. A method according to claim 1, wherein said radio-frequency radiation has a frequency from about 1 MHz to 100 MHz.

11. A method according to claim 1, wherein the average particle size of the specified powder mixture is less than 500 microns.

12. A method according to claim 1, wherein resorption of the said tablet in the mouth when placed on the tongue is less than about 30 seconds.

13. A method according to claim 1, wherein the specified hardness of the tablet is less than 700 grams according to the results obtained by using the texture analyzer TA-XT2i, equipped with a probe with a flat end face with a diameter of 7 millimeters.

14. A method according to claim 1, wherein the density of the specified tablet is less than 0.8 g/CC

15. A method according to claim 1, containing the following stages, where:
(i) impose specified the powder mixture in the molding cavity in said plate molds;
(ii) compress the specified powder blend by introducing at least one molding device to the specified plate of the mold with sufficient force for the formation of the preformed shape;
(iii) application of criminal code�cated radiation to said preformed shape in said molding cavity for the formation of the said tablets; and
(iv) removing the said tablet from said molding cavity.

16. A method according to claim 4, additionally containing a stage at which cooled the specified tablet in said mold before removing the said tablet from said mold.

17. A method according to claim 2, wherein said radiation is radio frequency radiation, and at least one specified sand specified device emits radio-frequency radiation on preformed specified form.

18. A method according to claim 2, wherein said radiation is radio frequency radiation, and the plate of the mold emits the specified radio-frequency radiation on preformed specified form.

19. A method according to claim 1, wherein said radiation is radio frequency radiation, the above-mentioned powder mixture is pressed using an upper moulder and bottom of the molding device, and at least one of the upper molding device or the bottom of the molding device emits the specified radio-frequency radiation on preformed specified form.

20. A method according to claim 1, wherein the surface of the said tablet further exposed to infrared radiation, with most of the wavelengths specified infrared radiation finds�I in the range from about 0.5 to about 5 micrometers.

21. Chewable tablet or oral-disintegrating tablet in the oral cavity, manufactured in accordance with the method according to claim 1.



 

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79 cl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for producing a tablet by (i) compressing a powder mixture in a mould plate of one device for producing a tabletted form with the powder mixture comprising a pharmaceutically active substance and a fusible binding agent, and (ii) exposing the above tabletted form to radio-frequency radiation generated by the above device over a period of time adequate to soften or melt the binding agent inside the above tabletted form to produce a tablet. Oral absorption of the produced tablet placed on the tongue takes less than approximately 30 s.

EFFECT: more effective method for producing the tablet by (i) compression.

18 cl, 14 dwg, 7 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention provides a composition having antioxidant properties in the form of a tablet, comprising an active agent based on nicotinamide adenine dinucleotide in reduced form (NADH) and inert filling agents, characterised by that the active ingredient is a complex which is a mixture of 10 wt % NADH with 63 wt % vegetable fats, 17 wt % beeswax and 10 wt % chlorophyll, and the inert filling agents are in the form of microcrystalline cellulose, Macrogol 6000, intense sweetener and a food flavourant.

EFFECT: invention provides a new tablet form of NADH.

1 ex

FIELD: chemistry.

SUBSTANCE: as active component pharmaceutical composition contains dihydrochloride of 9-(2-morpholine ethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidasol, and as additional substances - fillers, binding, sliding and film coatings, in quantities, given in the invention formula. Composition can be made in form of solid medication form, mainly in form of tablets and capsules.

EFFECT: obtained solid medication forms satisfy the requirements of the State Pharmacopoeia.

7 cl, 2 dwg, 3 tbl, 14 ex

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